This is a continuation of a French Application 98 09221 filed on Jul. 20, 1998.
The present Application generally relates to the use of a polymer of acrylic type as a break-up or disintegration agent. It relates in particular to the use of a copolymer of acrylic type as disintegration agent or co-agent in a galenic form of tablet type, as well as a process for producing galenic forms of tablet type using such a copolymer as a disintegration agent or co-agent.
The agents most generally used for the production of galenic forms intended to disintegrate correspond to agents known as distintegration agents of the sodium carboxymethyl cellulose type, or to agents known as swelling agents of crospovidone or modified starch type.
While some of these agents allow tablets to be obtained which have a disintegration speed suited to the conditions in which they are used, while presenting acceptable pharmacotechnical characteristics (in particular hardness, friability and stability), this involves long and complex processes. In fact, the use of these agents as disintegration agents requires for example the creation of specific sub-structures such as microparticles or microgranules before the tablet is turned into its final galenic form, or the use of effervescent type reactions, which reactions themselves require the tablets to be manufactured in a low humidity medium.
The invention which is a subject of the present Application proposes a new use of a polymer of acrylic type and a new process which aims to remedy the drawbacks involved in the techniques of the prior art. The new use and the new process according to the invention also shows particularly appreciable performances for obtaining tablets which display appropriate disintegration properties under conditions of use or equivalent to this use while displaying very good pharmacotechnical characteristics (in particular hardness, friability, stability) before use and in particular during storage.
The polymers of acrylic type are, for their part, generally used in the prior art for the manufacture of sustained release tablets and/or for the production of enteric coatings. Among the different polymers of acrylic type known to a person skilled in the art, the US Pharmacopea National Formulary (USP/NF) makes a distinction in particular between methacrylic acid copolymers of type A, B or C and ammonium methacrylate copolymers of type A or B. It is in particular known that methacrylic acid copolymers of type A or B and ammonium methacrylate copolymers of type A or B can be used in the production of delay matrices (pH-dependent in the case of the first copolymers; pH-independent in the case of the second). The methacrylic acid copolymers of type C are for their part known as being able to be used in the production of different coatings: enteric coatings due to their gastro-resistent properties and their solubility in an intestinal medium at pH 5.5-7.5; insulation coatings intended to protect active ingredients in a tropical type environment; or also coatings intended to mask taste or smell.
The inventors have demonstrated that certain polymers of acrylic type, namely the methacrylic acid copolymers of type C according to the USP/NF, are, unexpectedly, capable of very significantly improving the disintegration speed of a tablet, while allowing a tablet to be obtained which has very good pharmacotechnical characteristics, and in particular very good cohesion. The use of a methacrylic acid copolymer of type C according to the invention has the particular advantage of allowing rapid disintegration tablets to be obtained, and in particular immediate type disintegration, which display, before use, very good pharmacotechnical characteristics (in particular, very good hardness and friability characteristics).
These very good pharmacotechnical characteristics simplify the packaging and storage of the tablets produced in this way: the tablets produced by means of the use or the process according to the invention do not require packaging specifically adapted to the protection of the structure of these tablets such as packaging with a peel-off film so as to avoid the extraction of the tablet from its cell by pushing with a finger.
These very good pharmacotechnical characteristics are also at the origin of the very good storage characteristics of said tablets over time (stability). These specific polymers of acrylic type according to the invention, in addition to the surprising disintegration effectiveness they offer, also have the notable advantage of being easy to use for producing tablets. In fact, they do not of themselves require the implementation of specific technologies to produce cohesive rapid disintegration tablets: any technology known to a person skilled in the art can be used, providing the other elements of the galenic form are chosen in such a manner as to allow this. In particular, they allow the production of cohesive rapid disintegration tablets by simple direct compression, without requiring the implementation of exacting technologies such as wet granulation.
A subject of the present Application is therefore, in general, the use of at least one methacrylic acid copolymer of type C according to the USP/NF as an agent or co-agent allowing the improvement of the disintegration speed of a tablet while allowing a tablet with a good cohesion to be obtained, in particular by simple direct compression. It relates in particular to the use of at least one methacrylic acid copolymer of type C according to the USP/NF as an agent or co-agent allowing or participating in the disintegration of a tablet, as well as a production process for tablets involving the use of at least one copolymer as a disintegration agent or co-agent in a tablet.
It relates in particular to the use of at least one methacrylic acid copolymer of type C according to the USP/NF as an agent or co-agent allowing or participating in rapid disintegration of immediate type of a tablet as well as a production process for rapid disintegration tablets, and in particular immediate disintegration tablets, using such a copolymer as a disintegration agent or co-agent.
The tablet disintegration effect observed according to the invention does not correspond to a simple erosion of mechanical type, but rather to an effect of the swelling type after appropriate hydration of the tablet.
By xe2x80x9ctablet disintegration agentxe2x80x9d is understood in the present Application an agent allowing an improvement in the disintegration speed observed for this tablet in the absence of this agent.
This improvement in tablet disintegration speed can naturally be optimized by choosing the other tablet characteristics (such as type and quantity of the tablet""s components, mass, format, hardness of the tablet) such that they do not oppose or even that they enhance the disintegration phenomenon.
By xe2x80x9crapid tablet disintegration agentxe2x80x9d is thus understood in the present Application an agent offering a significant improvement in the tablet""s disintegration speed, as indicated above. The term xe2x80x9csignificantxe2x80x9d can be appreciated using any statistical tool known to a person skilled in the art. Appropriate conditions for observing this significant improvement include those which consist in placing said tablet in medium conditions and in particular in composition, pH and temperature conditions suited to the disintegration of the tablet in question.
By xe2x80x9cimmediate type tablet disintegration agentxe2x80x9d is understood an agent allowing the disintegration of said tablet over a period lasting approximately 25 seconds or less, preferably approximately 20 seconds or less, even more preferably approximately 10 seconds or less, when the tablet is tested under conditions appropriate for its disintegration, and when the other components of the tablet and its structure (mass, format, hardness) are chosen in such a way that they do not oppose, or they even enhance, the disintegration phenomenon. Appropriate conditions for testing the disintegration of a tablet include conditions which mimic those under under which said tablet is intended to break up. For example, in the case of a tablet intended to break up under the physiological conditions of a buccal cavity, such appropriate conditions include the fact of testing said tablet on an apparatus of Erweka ZT3(copyright) type in a saliva medium at 33xc2x0 C. and pH 6.0.
The term xe2x80x9cagentxe2x80x9d used in the present Application also covers a co-agent situation. Thus the use according to the invention advantageously includes the use of a methacrylic acid copolymer of type C according to the USP/NF as an immediate type disintegration agent according to the invention, combined with the use of one or more known disintegration agents such as crospovidone (for example, that marketed under the trade mark Kollidon-CL(copyright) by BASF Aktiengesellschaft, Ludwigshafen, Germany).
The methacrylic acid copolymer(s) of type C used as disintegration agent(s) or co-agent(s) according to the invention can in particular be used for the production of any tablet requiring an improvement in the disintegration speed, and in particular a high disintegration speed. This is in particular the case for tablets adapted or intended for a pharmaceutical, veterinary or hygiene use. There can in particular be mentioned pharmaceutical, veterinary or hygiene tablets intended for administration by oral route for disintegration in the buccal cavity, those intended for administration by oral route for deferred disintegration, for example deferred to the level of the intestines, or also those intended for administration by vaginal route.
The present Application relates in particular to the use of a methacrylic acid copolymer of type C according to the USP/NF in a tablet intended to break up rapidly (of immediate type) in the buccal cavity. Such a copolymer thus used or implemented or as a disintegration agent (or co-agent) in fact allows tablets to be obtained which are capable (after hydration with saliva) of breaking up in the buccal cavity over a very short period of time (in a particularly preferential manner, periods of less than 10 seconds are obtained). The suspension created in this way benefits from a large exchange surface, and the active ingredients are released in a particularly rapid manner. Apart from the usefulness of this galenic form in terms of bioavailability, it has other advantages, one of the main advantages undoubtedly being its ease of use. In fact, the patient needs no water in order to follow his treatment, resulting in better observance. For young children or the elderly, this form also requires no chewing or deglutition effort.
The buccal disintegration tablets can however have the drawback of an unpleasant taste and/or smell. In order to reduce or even eliminate the unpleasant smell and/or taste of the galenic form, sweeteners and/or flavourings can be added to the formulation, and/or those components which have an unpleasant taste and/or smell can be coated (for example, the active ingredient can be coated). Remarkably, such components modified by coating can be included in the use according to the invention without significantly modifying its disintegration speed.
The proportions in which said (or each of said) methacrylic acid copolymer(s) of type C must be used according to the invention can easily be tested by trial and error using techniques known to a person skilled in the art, according to the complete formulation of the tablet chosen, and according to the effect sought. For information, these proportions are generally comprised between approximately 5 and 50% of the total mass of the tablet.
The methacrylic acid copolymer(s) of type C implemented, or used as disintegration agent(s) or co-agent(s) according to the invention do not cause any restriction in the possible nature of the other elements of the galenic form. It or they can thus be combined with any substance or excipient appropriate to the type of appliation for which the tablet is intended.
According to a provision of the invention, said use turns to good account the fact that the methacrylic acid copolymers of type C are both gastro-resistent and soluble in an intestinal medium in order to combine them with one or more copolymer(s) of ammonium methacrylate of type A and/or B according to the USP/NF (delay matrix independent of the pH), in order to encourage the release of the active ingredient in the intestine. The process and the use according to the invention then allow a tablet to be obtained intended for administration by oral route, which does not break up at the level of the intestines, in very short periods of time, or even over an immediate type of time period if necessary.
For an application by vaginal route, the use according to the invention can further comprise the implementation of a bioadhesive compound.
In a quite general manner, the use of at least one methacrylic acid copolymer of type C according to the invention further comprises the use of an active ingredient or a placebo, the use of a diluent (such as dextrose), of a hardness enhancing agent (such as sorbitol), of a lubricant (such as magnesium stearate or groundnut oil), and optionally a binding agent (such as maize starch).
More particularly, the use according to the invention can also further comprise the use of excipients or substances among those playing the following roles:
disintegration or disintegration agents such as for example crospovidone (marketed under the trademark Kollidon-CL(copyright) for example), sodium croscarmellose, sodium carboxymethyl starch, partially substituted hydroxypropylcellulose, sodium starch glycolate, in a proportion which can vary from 1% to 50%,
soluble or slightly soluble swelling agents,
diluents such as lactose,
binding agents such as maize starch,
lubricants such as magnesium stearate,
flow agents such as colloidal silica,
solubilization agents,
flavourings,
sweeteners,
plastifiers,
antioxidants,
film forming and coating agents,
agents involved in the composition of the polishing and shining solution,
agents providing thermal protection of the active ingredient such as saccharose derivatives,
excipients or substances providing bioadhesion such as
acrylic acid derivatives, the copolymer of methylvinylether and maleic anhydride, guar gum, xanthane gum, carouba, carraghenates, pectin, a biological or synthetic protein alone or in combination with other proteins of biological or synthetic origin, cyclodextrins, hydroxypropylbetacyclodextrins, betacyclodextrins and their derivatives.
The use according to the invention allows any desired active ingredient to be combined with the tablet. There can in particular be mentioned antihistamines, anticholergenics, mineral elements, allergens, surface, local or general anesthetics, antipyretics, non-opiate analgesics, opiate analgesics, anticholinergic and non-anticholinergic antispasmodics, non-steroid anti-inflammatories such as tiaprofenic acid, indomethacin, diclofenac, ibuprofen, ketoprofen, naproxen, piroxicam, steroid anti-inflammatories such as betamethasone, prednisolone, cytotoxics, antihormonal agents, antianaemics, antiemetics, antiasthenics, antihypertensives including beta-blockers such as propranolol, atenolol, metoprolol, conversion enzyme inhibitors such as captopril, enalapril, angiotensin II antagonists, calcium inhibitors such as nifedipine and diltiazem, central action antihypertensives, vasodilators, hypolipemiants, oral antidiabetics, anticoagulants, platelet antiaggregants, calcium inhibitors, nitrated derivatives used in the treatment of coronary insufficiency, non-nitrated antianginals, diuretics, digitalin derivatives and related derivatives, antiarhythmics, antihypotensives and circulatory analeptics, vasodilators, anti-ischemics, vasculoprotectors and venotonics, hormones, antiherpetics, antiphotosensitizers, antiulceratives such as ranitidine, cimetidine, antacids, laxatives, antidiarrheals, antifungals, cholelitholytics, interferons, enzymes, antispasmodics, antibacterials, antiseptics, antiherpetics, uterorelaxants, oxytocics, oestrogens, progestatives, oestroprogestatives, the active ingredients indicated in lactation such as bromocriptine, the active ingredients indicated in the treatment of sterility, antigonadotropics, anticoagulants, thrombolytics, antifibrinolytics, vitamins, haemostatics, cyclosporines, alkylating agents, antibiotics, antivirals, antiparasitics, vaccines, diagnostic products, the active ingredients indicated in the treatment of obesity, orexigenics, the active ingredients indicated in the treatment of the correction of metabolic abnormalities, the active ingredients indicated in oral and enteral nutrition, anticonvulsives, antiparkinsonians, antimyasthenics, the active ingredients indicated in the treatment of Alzheimer""s disease, antimigraine agents, neuroleptics, anxiolytics, hypnotics, sedatives, antidepressants, normothymrics, psychostimulants, the active ingredients indicated in the treatment of states of alcohol addiction, tobacco disintoxication, opiate disintoxication, antiglaucoma agents, mydriatics, bronchodilators, antiasthmatics, antitussives, bronchial fluidifiers, (topical) revulsives, the active ingredients indicated in the treatment of osteopathies, the active ingredients indicated in the treatment of acute attacks of gout, the active ingredients indicated in the treatment of hypouricemia, the active ingredients indicated in the treatment of algodystrophiae, myorelaxants, the active ingredients indicated in the treatment of arthrosis, correctors of hyposialoses, the active ingredients indicated in the treatment of urinary lithiasis, the active ingredients indicated in the treatment of renal insufficiency, the active ingredients indicated in the treatment of enuresis, the active ingredients indicated in the treatment of retrograde ejaculation, the active ingredients indicated in the treatment of impotence.
The methacrylic acid copolymer(s) of type C according to the USP/NF used as a disintegration agent according to the invention can be incorporated by mixture into the tablet mass, or can only be part of certain sub-structures of the tablet, for example be incorporated with micro- or nano-particles (or micro- or nano-capsules) included in a tablet, and/or be incorporated into a layer of a multi-layer tablet, in particular in a layer intended for rapid disintegration. This tablet, intended for rapid disintegration, whether mono-layered, particular, multi-layered or a combination of these arrangements, is advantageously presented in the form of a bioadhesive tablet (for example, for rapid disintegration by vaginal route), and/or a tablet for the rapid but deferred release of the active ingredient(s) (for example, rapid disintegration at the level of the intestines after administration by oral route), or a tablet for the rapid and immediate release of the active ingredient(s) (for example, rapid disintegration in the mouth).
The at least one methacrylic acid copolymer of type C and the other disintegration agent(s) are present in a weight ratio of about 1:10 to about 1:1 to about 50:1. It is advantageous that the at least one methacrylic acid copolymer of type C be present in an amount that is at least about the same (i.e. 50:50) or that is greater than that of the other disintegration agents, with a ratio of 2:1 being preferred as shown in the examples.
Advantageously, the use according to the invention comprises a use of said tablet mass, or, where appropriate, of said tablet sub-structure in an essentially pulverulent form before being turned into a galenic form.
The use of a methacrylic acid copolymer of type C as a disintegration agent of a tablet according to the invention allows said tablet to be obtained (or, where appropriate, allows said tablet sub-structure to be obtained in which said copolymer is incorporated) using any technique known to a person skilled in the art, such as wet granulation, dry granulation and compacting, extrusion, as well as, advantageously, such as direct compression. Restriction to one or more types of technique can be observed according to the nature and/or proportion of the other components used in the production of said tablet, and/or according to the structure to be given to this tablet. Such a restriction is however not a result of said methacrylic acid copolymer of type C used. Preferentially, the use according to the invention comprises turning said tablet, or, where appropriate, said tablet sub-structure into galenic form, by simple direct compression.
Remarkably, the use according to the invention allows tablets to be obtained which have very good pharmacotechnical characteristics and which in particular, after being turned into a galenic form, display a hardness comprised between approximately 0.2 and 10 Kp and a friability comprised between approximately 0 and 25%.
The use according to the invention is suited to the production of tablets of any mass and any format, without limitation. Typically, for medical, veterinary or hygiene uses, tablet masses ranging from 50 to 200 mg are produced and formats of D6R4, flat D6, D7R5, D9R7, flat D9, flat D10 type are used.
Particularly remarkably, the use according to the invention allows tablets to be obtained which, while having very good pharmacotechnical characteristics, are capable of breaking up in a time period of less than approximately 25 seconds, preferably in a time period less than or equal to approximately 20 seconds, even more preferably less than or equal to approximately 10 seconds, when they are placed in appropriate conditions for their disintegration. The determination of appropriate conditions is known to a person skilled in the art, and examples of this are given in the present Application.
Examples of methacrylic acid copolymers of type C according to the USP/NF which can be used according to the invention include those marketed by the company Rxc3x6hm GmbH (Darmstadt, Germany), under the name Eudragit L100-55(copyright) (pulverulent form), or Eudragit L30D-55(copyright) (aqueous dispersion). Eudragit L100-55(copyright) corresponds to the following formula: 
A subject of the present invention is also production process for tablets, in particular rapid disintegration tablets, and in particular immediate type rapid disintegration tablets, said process involving the use of at least one methacrylic acid copolymer of type C according to the USP/NF as a disintegration agent or co-agent, and in particular involving the use of at least one methacrylic acid copolymer of type C as used according to the invention. Preferentially and advantageously, the process according to the invention further comprises turning the tablets into galenic form by simple direct compression.